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Digital gene expression (DGE) technologies measure gene expression by counting sequence tags. They are sensitive technologies for measuring gene expression on a genomic scale, without the need for prior knowledge of the genome sequence. As the cost of DNA sequencing decreases, the number of DGE datasets is expected to grow dramatically. Various tests of differential expression have been proposed for replicated DGE data using over-dispersed binomial or Poisson models for the counts, but none of the these are usable when the number of replicates is very small. We develop tests using the negative binomial distribution to model overdispersion relative to the Poisson, and use conditional weighted likelihood to moderate the level of overdispersion across genes. A heuristic empirical Bayes algorithm is developed which is applicable to very general likelihood estimation contexts. Not only is our strategy applicable even with the smallest number of replicates, but it also proves to be more powerful than previous strategies when more replicates are available. The methodology is applicable to other counting technologies, such as proteomic spectral counts.